Control of Adipogenesis by Arginine Methyltransferases

Univ Of Massachusetts Med Sch Worcester, Worcester MA

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Abstract

DESCRIPTION (provided by applicant): The prevalence of obesity and its complications, including metabolic diseases such as diabetes, are ever growing and major health concerns. Much effort has been focused on defining the formation and function of adipose tissue and progress has been made in defining specific genes involved in the regulation of adipose. The adipose tissue is an endocrine organ whose development at the molecular level is a topic of intense investigation, and indeed it is becoming increasingly appreciated that differentiation events leading to mature adipocytes involve a coordinate regulation of a large variety of genes that are essential for adipose development. However, epigenetic modulation of adipose products by factors including transcription factors, histone modifiers, and ATP-dependent chromatin remodelers, is much less well-understood. Pharmacological regulation of these factors has shown to be effective in the context of cancer and epilepsy, for example by histone deacetylase inhibitors, and similarly may be applicable to health concerns such as diabetes and obesity. In our current study, we have found that the protein arginine methyltransferase, Prmt5, is required for the expression of adipogenic hormones as well as the generation of large lipid droplets associated with adipogenesis, and that there is evidence for direct binding of Prmt5 at adipogenic targets. Binding of the chromatin remodeling enzyme Brgl, an ATPase of the SWI/SNF family of remodeling complexes, is also Prmt5-dependent at these promoters. Based on these preliminary data, we will define the requirements for Prmt5 and SWI/SNF in adipose differentiation, examine the functional role of SWI/SNF at adipogenic promoters, explore the interplay between Prmt5 and another arginine methyltransferase, as well as directly evaluate these factors in adipose tissue by in vivo electroporation. Relevance: Determining how methyltransferases regulate gene expression is critical in elucidating their role in conditions such as obesity and diabetes. Identifying the molecular mechanisms by which these factors control adipogenesis will greatly enhance our understanding of the regulatory events that are required for adipose development, and may lead to new avenues for therapeutic intervention.